Tramadol hydrochloride extended release

Overdose

Acute overdosage with tramadol can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, bradycardia, hypotension, and death.

Deaths due to overdose have been reported with abuse and misuse of tramadol, by ingesting, inhaling, or injecting the crushed tablets. Review of case reports has indicated that the risk of fatal overdose is further increased when tramadol is abused concurrently with alcohol or other CNS depressants, including other opioids.

In the treatment of tramadol overdosage, primary attention should be given to the reestablishment of a patent airway and institution of assisted or controlled ventilation. Supportive measures (including oxygen and vasopressors) should be employed in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation. While naloxone will reverse some, but not all, symptoms caused by overdosage with tramadol, the risk of seizures is also increased with naloxone administration. In animals, convulsions following the administration of toxic doses of Tramadol Hydrochloride Extended Release™ could be suppressed with barbiturates or benzodiazepines but were increased with naloxone. Naloxone administration did not change the lethality of an overdose in mice. Hemodialysis is not expected to be helpful in an overdose because it removes less than 7% of the administered dose in a 4-hour dialysis period.

Contraindications

Tramadol Hydrochloride Extended Release™ is contraindicated in patients who have previously demonstrated hypersensitivity to tramadol, any other component of Tramadol Hydrochloride Extended Release™, or opioids. Reactions range from pruritis to fatal anaphylactoid reactions.

Tramadol Hydrochloride Extended Release™ is contraindicated in patients with significant respiratory depression in unmonitored settings or the absence of resuscitative equipment.

Tramadol Hydrochloride Extended Release™ is contraindicated in patients with acute or severe bronchial asthma or hypercapnia in unmonitored settings or the absence of resuscitative equipment.

Pharmaceutical form

Undesirable effects

The following serious or otherwise important adverse reactions are described in greater detail, in other sections:

• Seizure risk
• Suicide risk
• Serotonin syndrome
• Anaphylactoid and allergic reactions
• Respiratory depression
• Withdrawal symptoms

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Tramadol Hydrochloride Extended Release™ capsules were administered to a total of 1987 patients in clinical trials. These included four double-blind and one long-term, open-label study in patients with osteoarthritis of the hip and knee. A total of 812 patients were 65 years or older. Adverse reactions with doses from 100 mg to 300 mg in the four pooled, randomized, doubleblind, placebo-controlled studies in patients with chronic non-malignant pain are presented in the following table (see Table 1).

Table 1: Incidence (%) of patients with adverse reaction rates ≥ 5% from four doubleblind, placebo controlled studies in patients with moderate to moderately severe chronic pain by dose (N=1917).

The following adverse reactions were reported from all chronic pain studies (N=1917). The lists below include adverse reactions not otherwise noted in Table 1.

Cardiac disorders: hypertension

Gastrointestinal disorders: dyspepsia, flatulence

General disorders: abdominal pain, accidental injury, chills, fever, flu syndrome, neck pain, pelvic pain

Investigations: hyperglycemia, urine abnormality

Metabolism and nutrition disorders: peripheral edema, weight loss

Musculoskeletal, connective tissue and bone disorders: myalgia

Nervous system disorders: paresthesia, tremor, withdrawal syndrome

Psychiatric disorders: agitation, anxiety, apathy, confusion, depersonalization, depression, euphoria, nervousness

Respiratory, thoracic and mediastinal disorders: bronchitis, pharyngitis, rhinitis, sinusitis

Skin and subcutaneous tissue disorders: rash

Urogenital disorders: prostatic disorder, urinary tract infection

Vascular disorders: vasodilatation

Adverse reactions with incidence rates of 0.5% to < 1.0% at any dose and serious adverse reactions reported in at least two patients.

Cardiac disorders: EKG abnormal, hypotension, tachycardia

Gastrointestinal disorders: gastroenteritis

General disorders: neck rigidity, viral infection

Hematologic/Lymphatic disorders: anemia, ecchymoses

Metabolism and nutrition disorders: blood urea nitrogen increased, GGT increased, gout, SGPT increased

Musculoskeletal disorders: arthritis, arthrosis, joint disorder, leg cramps

Nervous system disorders: emotional lability, hyperkinesia, hypertonia, thinking abnormal, twitching, vertigo

Respiratory disorders: pneumonia

Skin and subcutaneous tissue disorders: hair disorder, skin disorder, urticaria

Special Senses: eye disorder, lacrimation disorder

Urogenital disorders: cystitis, dysuria, sexual function abnormality, urinary retention

Therapeutic indications

Tramadol Hydrochloride Extended Release™ is indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period of time.

Pharmacodynamic properties

Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in clinical studies.

Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left ventricular function or cardiac index. Orthostatic hypotension has been observed.

Pharmacokinetic properties

The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. Tramadol Hydrochloride Extended Release™ is administered as a racemate and both tramadol and M1 are detected in the circulation. The Cmax and AUC of Tramadol Hydrochloride Extended Release™ capsules have been observed to be dose-proportional over an oral dose range of 100 to 300 mg in healthy subjects.

After a single dose administration of Tramadol Hydrochloride Extended Release™, Tmax occurs around 10-12 hours.

The mean Cmax and AUC of Tramadol Hydrochloride Extended Release™ capsules after a 300 mg single dose was 308 ng/Ml and 6777 ng*hr/mL, respectively under fasting conditions. Tramadol Hydrochloride Extended Release™ is bioequivalent to a reference extended-release tramadol product following a single 300 mg dose under fasting conditions.

At steady-state, Tramadol Hydrochloride Extended Release™ at 200 mg has been observed to be bioequivalent to a reference extended-release tramadol product at 200 mg under fasting conditions (Table 2). Following administration of Tramadol Hydrochloride Extended Release™ 200 mg capsules, steady-state plasma concentrations of both tramadol and M1 are achieved within four days of once daily dosing.

Figure 2 : Mean (%CV) Steady-State Pharmacokinetic Parameter Values (N=38)

The rate and extent of absorption of Tramadol Hydrochloride Extended Release™ capsules (300 mg) are similar following oral administration with or without food. Therefore, Tramadol Hydrochloride Extended Release™ capsules can be administered without regard to meals.

The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100 mg intravenous tramadol dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.

Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N – (mediated by CYP3A4 and CYP2B6) and O – (mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyl tramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition and polymorphism, which may affect the therapeutic response.

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The mean plasma elimination half-lives of racemic tramadol and racemic M1 after administration of Tramadol Hydrochloride Extended Release™ capsules are approximately 10 and 11 hours, respectively.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Concomitant use of tramadol increases the seizure risk in patients taking:

• Selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors (SNRIs) antidepressants or anorectics,
• Tricyclic antidepressants (TCAs), and other tricyclic compounds (e.g., cyclobenzaprine, promethazine, etc.),
• Other opioids,
• MAO inhibitors ,
• Neuroleptics, or
• Other drugs that reduce the seizure threshold.

Risk of seizures may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections).

In tramadol overdose, naloxone administration may increase the risk of seizure.

• Do not prescribe Tramadol Hydrochloride Extended Release™ for patients who are suicidal or addiction-prone. Consideration should be given to the use of non-narcotic analgesics in patients who are suicidal or depressed.
• Prescribe Tramadol Hydrochloride Extended Release™ with caution for patients with a history of misuse and/or are taking CNS-active drugs including tranquilizers or antidepressant drugs, or alcohol in excess, and patients who suffer from emotional disturbance or depression.
• Tell your patients not to exceed the recommended dose and to limit their intake of alcohol.

The development of a potentially life-threatening serotonin syndrome may occur with use of tramadol products, including Tramadol Hydrochloride Extended Release™, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs and triptans, with drugs which impair metabolism of serotonin (including MAOIs) and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur within the recommended dose..

Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving therapy with tramadol. When these events do occur it is often following the first dose. Other reported allergic reactions include pruritus, hives, bronchospasm, angioedema, toxic epidermal necrolysis and Stevens-Johnson syndrome. Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Tramadol Hydrochloride Extended Release™.

Administer Tramadol Hydrochloride Extended Release™ cautiously in patients at risk for respiratory depression. In these patients alternative non-opioid analgesics should be considered. If large doses of tramadol are administered with anesthetic medications or alcohol, respiratory depression may result. Respiratory depression should be treated as an overdose. If naloxone is to be administered, use cautiously because it may precipitate seizures.

Tramadol may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Use Tramadol Hydrochloride Extended Release™ with caution and in reduced dosages when administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents, narcotics, phenothiazines, tranquilizers or sedative hypnotics. Tramadol Hydrochloride Extended Release™ increases the risk of CNS and respiratory depression in these patients. Alcohol-containing beverages should not be consumed by patients using Tramadol Hydrochloride Extended Release™.

Use Tramadol Hydrochloride Extended Release™ with caution in patients with increased intracranial pressure or head injury. The respiratory depressant effects of opioids include carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure, and may be markedly exaggerated in these patients. Additionally, pupillary changes (miosis) from tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental status in these patients if they are receiving Tramadol Hydrochloride Extended Release™.

Tramadol Hydrochloride Extended Release™ may impair the mental and or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Caution patients initiating therapy with Tramadol Hydrochloride Extended Release™ or those whose dose has been increased to refrain from potentially hazardous activities until it is established that their mental and physical abilities are not significantly impaired.

Use Tramadol Hydrochloride Extended Release™ with great caution in patients taking monoamine oxidase inhibitors. Animal studies have shown increased deaths with combined administration. Concomitant use of Tramadol Hydrochloride Extended Release™ with MAO inhibitors or SSRI's increases the risk of adverse reactions, including seizure and serotonin syndrome.

Withdrawal symptoms may occur if Tramadol Hydrochloride Extended Release™ is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Clinical experience with other formulations of tramadol suggests that withdrawal symptoms may be reduced by tapering Tramadol Hydrochloride Extended Release™ when discontinuing tramadol therapy.

Tramadol Hydrochloride Extended Release™ contains tramadol, an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

Tramadol can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing Tramadol Hydrochloride Extended Release™ in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion.

Tramadol Hydrochloride Extended Release™ could be abused by crushing, chewing, snorting, or injecting the dissolved product. These practices will result in the uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and death.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. The development of addiction to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of addiction in chronic pain patients. Healthcare professionals should contact their State Professional Licensing Board, or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Serious potential consequences of overdosage with Tramadol Hydrochloride Extended Release™ are central nervous system depression, respiratory depression and death. In treating an overdose, primary attention should be given to maintaining adequate ventilation along with general supportive treatment.

The administration of Tramadol Hydrochloride Extended Release™ may complicate the clinical assessment of patients with acute abdominal conditions.

There are no adequate and well-controlled studies in pregnant women. Use Tramadol Hydrochloride Extended Release™ during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Neonatal seizures, neonatal withdrawal syndrome, fetal death and still birth have been reported during post-marketing reports with tramadol HCl immediate-release products. Â Tramadol Hydrochloride Extended Release™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Tramadol was not teratogenic at oral dose levels up to 50 mg/kg/day (1.6-fold the maximum daily human dose (MDHD)) in rats and 100 mg/kg (approximately 6.5-fold MDHD) in rabbits during organogenesis. However, embryo-fetal lethality, reductions in fetal weight and skeletal ossification, and increased supernumerary ribs were observed at a maternal toxic dose of 140 mg/kg in mice (approximately 2.3-fold MDHD), 80 mg/kg in rats (2.6-fold MDHD) or 300 mg/kg in rabbits (approximately 19-fold MDHD).

Tramadol caused a reduction in neonatal body weight at a dose of 50 mg/kg (1.6-fold the MDHD) and reduced pup survival at an oral dose of 80 mg/kg (approximately 2.6-fold MDHD) when rats were treated during late gestation throughout lactation period.

Tramadol Hydrochloride Extended Release™ should not be used in pregnant women prior to or during labor unless the potential benefits outweigh the risks. Safe use in pregnancy has not been established. Chronic use during pregnancy may lead to physical dependence and post-partum withdrawal symptoms in the newborn. Tramadol has been shown to cross the placenta. The mean ratio of serum tramadol in the umbilical veins compared to maternal veins was 0.83 for 40 women given tramadol during labor.

The effect of Tramadol Hydrochloride Extended Release™, if any, on the later growth, development, and functional maturation of the child is unknown.

Tramadol Hydrochloride Extended Release™ is not recommended for obstetrical preoperative medication or for postdelivery analgesia in nursing mothers because its safety in infants and newborns has not been studied. Following a single IV 100 mg dose of tramadol, the cumulative excretion in breast milk within 16 hours post-dose was 100 μg of tramadol (0.1% of the maternal dose) and 27 μg of M1. It is not known whether this drug is excreted in human milk following an oral dose.

The safety and efficacy of Tramadol Hydrochloride Extended Release™ in patients under 18 years of age have not been established. The use of Tramadol Hydrochloride Extended Release™ in the pediatric population is not recommended.

In general, caution should be used when selecting the dose for an elderly patient. Usually, dose administration should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Eight hundred and twelve elderly (65 years of age or older) subjects were exposed to Tramadol Hydrochloride Extended Release™ in clinical trials. Of those subjects, two hundred and forty were 75 years of age and older. In general, higher incidence rates of adverse events were observed for patients older than 65 years of age compared with patients 65 years and younger, particularly for the following adverse events: nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia sweating, fatigue, weakness, postural hypotension and dyspepsia. For this reason, Tramadol Hydrochloride Extended Release™ should be used with great caution in patients older than 75 years of age.

Tramadol Hydrochloride Extended Release™ has not been studied in patients with renal impairment. Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The limited availability of dose strengths of Tramadol Hydrochloride Extended Release™ does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, Tramadol Hydrochloride Extended Release™ should not be used in patients with severe renal impairment.

Tramadol Hydrochloride Extended Release™ has not been studied in patients with hepatic impairment. The limited availability of dose strengths of Tramadol Hydrochloride Extended Release™ does not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Therefore, Tramadol Hydrochloride Extended Release™ should not be used in patients with severe hepatic impairment.

Dosage (Posology) and method of administration

Tramadol Hydrochloride Extended Release™ is an extended-release formulation intended for once a day dosing in adults aged 18 years and older. The tablets must be swallowed whole with liquid and must not be split, chewed, dissolved or crushed. Chewing, crushing or splitting the tablet could result in the uncontrolled delivery of tramadol, in overdose and death.

Do not administer Tramadol Hydrochloride Extended Release™ at a dose exceeding 300 mg per day. Do not use Tramadol Hydrochloride Extended Release™ more than once daily or concomitantly with other tramadol products.

Initiate treatment with Tramadol Hydrochloride Extended Release™ at a dose of 100 mg once daily and titrated up as necessary by 100 mg increments every five days to achieve a balance between relief of pain and tolerability.

Calculate the 24-hour tramadol IR dose and initiate a total daily dose of Tramadol Hydrochloride Extended Release™ rounded down to the next lowest 100 mg increment. The dose may subsequently be individualized according to patient need. Due to limitations in flexibility of dose selection with Tramadol Hydrochloride Extended Release™, some patients maintained on tramadol IR products may not be able to convert to Tramadol Hydrochloride Extended Release™.

Initiate dosing of an elderly patient (over 65 years of age) should be initiated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy. Tramadol Hydrochloride Extended Release™ should be administered with even greater caution in patients over 75 years, due to the greater frequency of adverse events seen in this population.

The limited availability of dose strengths and once daily dosing of Tramadol Hydrochloride Extended Release™ do not permit the dosing flexibility required for safe use in patients with severe renal impairment. Do not use Tramadol Hydrochloride Extended Release™ in patients with creatinine clearance less than 30 mL/min.

The limited availability of dose strengths and once daily dosing of tramadol hydrochloride extended-release capsules do not permit the dosing flexibility required for safe use in patients with severe hepatic impairment. Do not use Tramadol Hydrochloride Extended Release™ in patients with severe hepatic impairment (Child-Pugh Class C).

Withdrawal symptoms may occur if Tramadol Hydrochloride Extended Release™ is discontinued abruptly. Clinical experience with tramadol suggests that withdrawal symptoms may be reduced by tapering Tramadol Hydrochloride Extended Release™.

Tramadol Hydrochloride Extended Release™ may be taken without regard to food.